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研究生:林衡道
研究生(外文):Heng-Dao Lin
論文名稱:探討DNA損傷反應與慢性暴露4-胺基聯苯產生之肝臟毒性
論文名稱(外文):DNA Damage Response and Chronic Liver Toxicity Resulting from Exposure to 4-Aminobiphenyl
指導教授:陳師慶王紹文
指導教授(外文):Ssu-Ching ChenShao-Win Wang
學位類別:博士
校院名稱:國立中央大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:中文
論文頁數:155
中文關鍵詞:4-胺基聯苯微小RNADNA修補氧化壓力肝細胞癌斑馬魚
外文關鍵詞:4-AminobiphenylmicroRNADNA repairoxidative stressHCCzebrafish
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4-胺基聯苯 (4-ABP)是一種人類膀胱致癌物,常見於偶氮染料及香菸、環境污染物產生的煙霧中。我們先前的研究發現4-ABP可在HepG2細胞誘導DNA損傷,顯示4-ABP可對人類肝細胞造成遺傳毒性。此外,流行病學調查也間接指出4-ABP可能對人類肝臟產生影響,但目前對於4-ABP是否對於人類肝臟產生致癌作用仍具有爭議。我們的目標是研究4-ABP短期高劑量暴露下產生的DNA損傷反應之分子機制以及長期低劑量暴露後是否可誘導肝癌產生。在第一部分,我們以L-02,HepG2和Hep3B等作為測試模型探討ROS及miRNA是否可參與4-ABP在人類肝細胞誘導的DNA損傷反應。實驗結果顯示高劑量4-ABP可誘導肝細胞產生ROS,並通過調節miR-513a-5p和miR-630的表現量進而抑制DNA同源重組修復活性。在第二部分中,我們利用人類肝細胞株和斑馬魚建立了肝細胞癌變模型,以模擬長期暴露於低劑量的4-ABP(1 nM-10 µM)的肝癌發展。結果表明,低劑量4-ABP長期暴露可促進肝細胞增殖和遷移。此外, HBx, Src(p53-)轉基因斑馬魚暴露3個月4-ABP後及野生型斑馬魚中暴露6個月4-ABP都發現肝細胞癌形成。我們同時也發現細胞及斑馬魚模型中Ras-ERK途徑活化與4-ABP誘導的肝細胞癌之間的相關性。這些結果表明4-ABP可對肝臟產生遺傳毒性並促進肝細胞癌進展。據我們所知,這是首份關於慢性4-ABP暴露後促進人類細胞和斑馬魚產生肝癌之研究。
4-Aminobiphenyl (4-ABP) is a recognized human urinary bladder carcinogen that was commonly found in the manufacture of azo dyes, the compositions of cigarette smoke or polluted air. In our previous study, we found 4-ABP can induce DNA damage in HepG2 cells. Many epidemiologic studies have investigated the potential effects of 4-ABP on liver, but the oncogenic effect of 4-ABP on human liver remains controversial. Our purpose is to investigate the molecular mechanism of DNA damage response after acute 4-ABP treatment and whether 4-ABP induced liver carcinogenesis after chronic exposure. In the first part of our studies, we used human liver cells like L-02, HepG2 and Hep3B as a test model to investigate whether the ROS and miRNA affect DNA damage response during exposure to various concentrations of 4-ABP (75-300 µM) for 24 h. Our results showed that 4-ABP induces ROS production which inhibiting DNA homologous recombination (HR) repair activity via regulated miR-513a-5p and miR-630 expression. In the second part, we have established a liver cell carcinogenesis model in human liver cell lines and zebrafish to mimic liver cancer development associated with long-term exposure to low doses of 4-ABP (1 nM-10 µM). The results demonstrated that chronic 4-ABP exposure promoted cellular proliferation and migration in vitro. In addition, 4-ABP induces hepatocellular carcinoma (HCC) formation in HBx, Src (p53-) transgenic zebrafish at four months of age and in wild-type zebrafish at seven months of age. We also observed a correlation between the Ras-ERK pathway and 4-ABP-induced HCC in vitro and in vivo. These results indicated that 4-ABP has effects on genotoxicity in liver and HCC progression. To our knowledge, this is the first report on the promotion of liver carcinogenesis in human cells and zebrafish following 4-ABP exposure.
Table of Contents
Page
Declaration I
Publications II
(A). Referred papers: II
(B). Abstracts presented in meetings: III
中文摘要 IV
Abstract V
Acknowledgments VI
Table of Contents VII
List of Figures X
List of Tables XIV
Abbreviations XV
Chapter 1: General Introduction 1
1-1. 4-Aminobiphenyl (4-ABP) 1
Overview of 4-ABP 1
Bioactivation and genotoxicity of 4-ABP 2
Genetic toxicity assessment of aromatic amine using liver cells 4
The association between miRNA and DNA repair during exposure to 4-ABP 5
The potential link between 4-ABP and HCC 5
1-2. The interplay between ROS and miRNA in DNA damage response 7
Reactive oxygen species (ROS) 7
Micro RNA (miRNA) 8
ROS and miRNA 9
1-3. DNA damage response (DDR) 9
Aromatic amines and DNA damage 9
DNA damage response 10
DNA double-strand breaks repair 10
The role of p53 in DNA damage response 12
The role of MCM8-9 complex in DNA repair 13
1-4. Human liver cancer 14
Overview of liver cancer 14
The risk factor of HCC 14
Oxidative stress and inflammation contribute to HCC 15
1-5. Zebrafish liver cancer model 16
Overview of Zebrafish in liver disease model 16
Zebrafish cancer model 17
Xenotransplantation of zebrafish 18
1-6. Specific aim of the thesis 18
Chapter 2: Material and methods 21
2-1. Cell culture and transfection 21
2-2. Cell viability assay 21
2-3. Comet assay 21
2-4. RNA extraction, cDNA synthesis and qPCR 22
2-5. miRNA extraction 23
2-6. miRNA qPCR 23
2-7. Luciferase assay 23
2-8. ChIP assay 24
2-9. DNA HR activity assay 24
2-10. Cell cycle analysis 25
2-11. ROS assay 25
2-12. Protein extraction and Western blot 25
2-13. Colony formation assay 26
2-14. Soft agar formation 26
2-15. BrdU assay 27
2-16. Transwell assay 27
2-17. Zebrafish Maintenance and Transgenic Zebrafish Lines 27
2-18. Embryos Collection 28
2-19. Xenotransplantation of Hepatoma in Zebrafish 29
2-20. Body length, Weight Measurement and Liver Collection 29
2-21. Hematoxylin and eosin (H&E) staining 30
2-22. Immunohistochemistry Staining 31
2-23. Isolation of Zebrafish liver and RNA extraction 32
2-24. Hepatotoxicity test in zebrafish embryo 32
2-25. Embryotoxicity test 33
2-26. Statistical analysis 33
Chapter 3: Result 35
3-1. The epigenetic regulation of HR repair during exposure to 4-ABP 35
4-ABP-induced DNA double-strand breaks in liver cell lines 35
4-ABP regulated miRNA expression 35
4-ABP inhibit DNA HR repair via miR-513a-5p and miR-630 37
ROS plays a critical role in 4-ABP-induced DNA damage response 38
3-2. Chronic exposure to 4-ABP induce or promote hepatocarcinogenesis in vitro and in vivo 40
Effect of 4-ABP exposure on liver cells 40
Zebrafish xenotransplation model for 4-ABP chronic treated cells 42
H&E staining and IHC analysis of 4-ABP chronic treated zebrafish 43
Chapter 4: Discussion 47
4-1. Whether L-02, HepG2 and Hep3B cells can be used as a model to assessed the genotoxicity mechanism of 4-ABP? 47
4-2. DNA damage response and miR-513a-5p with 4-ABP treatment 48
4-3. DNA damage response and miR-630 with 4-ABP treatment 49
4-4. Oxidative stress and DNA damage response with 4-ABP treatment 52
4-5. The concentration of -4-ABP in the acute and chronic study 52
4-6. In vitro model of 4-ABP chronic exposure and xenotransplantation of the zebrafish embryo 53
4-7. Cytochrome P450 family in zebrafish 55
4-8. Chronic exposure to 4-ABP induce or promote hepatocarcinogenesis in the zebrafish model 56
Summary 57
Reference 58
Figures 77



List of Figures
Figure 1. Effects of 4-ABP on human liver cell viability. 77
Figure 2. Effect of 4-ABP on DNA damage in human liver cells. 78
Figure 3. Effect of 4-ABP on DNA DSBs in liver cells. 79
Figure 4. 4-ABP induces DSBs in liver cells. 80
Figure 5. Dysregulation of miR-513a-5p or miR-630 in liver cells after 4-ABP treatment. 81
Figure 6. p53 was predicted to bind to the promoter of miR-513a-5p. 82
Figure 7. CREB was predicted to bind to the 5’-UTR of miR-630 host gene ARIH1 and attenuated by NAC pretreatment during 4-ABP exposure. 83
Figure 8. miR-513a-5p mediates p53 expression in liver cells with 4-ABP treatment. 85
Figure 9. miR-513a-5p inhibitor or TP53 overexpression partially rescues DNA damage during exposure to 4-ABP. 87
Figure 10. Validation of genes involved in the p53 signaling pathway by qPCR. 88
Figure11. Validation of genes involved in the DNA double-strand break repair pathway. 89
Figure 12. miR-630 mediates MCM8 expression in liver cells with 4-ABP treatment. 90
Figure 13. RAD18 and MCM8 overexpression or miR-630 inhibitor partially inhibit 4-ABP-induced DNA DSBs. 91
Figure 14. miR-513a-5p inhibitor or TP53 overexpression partially rescues homologous recombination activity during 4-ABP exposure. 92
Figure 15. RAD18 and MCM8 overexpression or miR-630 inhibitor partially rescue DNA HR activity during 4-ABP exposure. 93
Figure 16. Effects of 4-ABP, miR-630 mimic or miR-630 inhibitor on the expression of MCM9. 94
Figure 17. 4-ABP induces S phase arrest in HepG2 and L-02 cells. 95
Figure 18. Transfection of pLenti-p53 or miR-513a-5p inhibitor rescue HepG2 or L-02 cells survival. 96
Figure 19. Transfection of pLenti-RAD18 or miR-630 inhibitor rescue HepG2 or Hep3B cells survival. 97
Figure 20. The ROS scavenger NAC suppressed ROS generation in liver cells during 4-ABP exposure. 98
Figure 21. NAC suppressed 4-ABP-induced DNA damage in liver cells. 99
Figure 22. NAC suppressed 4-ABP-induced DNA DSBs in liver cells. 100
Figure 23. NAC partially rescued DNA HR activity in liver cells during 4-ABP exposure. 101
Figure 24. NAC partially attenuates 4-ABP-induced miR-513a-5p and miR-630 expression in liver cells. 102
Figure 25. NAC partially rescued p53, RAD18 or MCM8 expression level in liver cells during 4-ABP exposure. 103
Figure 26. The effects of NAC on the expression of p53 or CREB during exposure to 4-ABP. 104
Figure 27. The effect of 4-ABP repeated treatment on human liver cells. 105
Figure 28. Progression of carcinogenesis induced by 4-ABP. 106
Figure 29. 4-ABP exposure for 20 cycles induced cell proliferation and migration. 108
Figure 30. GO (gene ontology) analysis of the differentially expressed genes in HepG2-ABP20 cells. 109
Figure 31. The KEGG enrichment analysis of differentially expressed genes in HepG2-ABP20 cells. 110
Figure 32. Overview of significant pathways in network marker in HepG2-ABP20 cells. 111
Figure 33. 4-ABP induced H-Ras expression level with 4-ABP repeated treatment. 112
Figure 34. 4-ABP exposure for 20 cycles upregulated RAS-MEK-ERK pathway protein expression level. 113
Figure 35. Low dose of 4-ABP induced ROS level in human liver cells. 114
Figure 36. NAC partially attenuates 4-ABP-induced induced carcinogenesis, cell proliferation and migration. 115
Figure 37. NAC partially attenuates 4-ABP-induced RAS protein expression level. 117
Figure 38. NAC partially attenuates 4-ABP-induced Ras-MEK-ERK pathway protein expression level. 118
Figure 39. 4-ABP repeated treatment increased human liver cell lines proliferation in the zebrafish embryo. 119
Figure 40. Embryonic toxicity assay for 4-ABP treatment of wild-type zebrafish or Tg(fabp10a: HBx, src, p53-/-). 121
Figure 41. LC50 test for 4-ABP treatment of wild-type zebrafish or Tg(fabp10a: HBx, src, p53-/-). 122
Figure 42. Hepatoxicity assay for 4-ABP treatment of WT zebrafish or Tg(fabp10a: HBx, src, p53-/-). 123
Figure 43. WT zebrafish or Tg(fabp10a: HBx, src, p53-/-) as model organism for studies of chronic exposure to 4-ABP. 124
Figure 44. 4-ABP induced hepatocarcinogenesis in WT or Tg(fabp10a: HBx, src, p53-/-) at 7 months of age. 125
Figure 45. Expression analysis of cell proliferation relating genes in liver of WT or Tg(fabp10a: HBx, src, p53-/-) at 4 and 7 months of age during exposure to 4-ABP. 126
Figure 46. The immunoreactive score (IRS) of immunohistochemistry for the proliferating cell nuclear antigen (PCNA) was greater in 4-ABP treatment group than in control group at 4 and 7 months of age. 127
Figure 47. Expression of inflammatory genes s in the liver of WT or Tg(fabp10a: HBx, src, p53-/-) at 4 and 7 months of age during exposure to 4-ABP. 128
Figure 48. The immunoreactive score (IRS) of immunohistochemistry for the p-ERK was greater in 4-ABP treatment group than in control group at 4 and 7 months of age. 129


List of Tables
Table 1. List of primer sequences for qPCR (F: Forward, R: Reverse) 130
Table 2. List of primer sequences for qPCR in zebrafish study 132
Table 3. List of gene-specific PCR primer sequences for cloning 133
Table 4. List of primer sequences for ChIP-qPCR 134


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